Radiographic Phenotypes Research Articles

Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes

For the first time the study provides evidence of association of radiographic hand bone length (BL) and bone mineral density (BMD) with polymorphisms in ROR2 gene that plays important role in skeletal development. This contributes to better understanding of bone physiology and may have application in clinical practice. Bone size and bone mineral density (BMD) are major determinants of bone strength. Identification of genes affecting these traits' variability is important for better understanding of normal and pathological bone physiology and identification of the individuals at risk for bone fracture. This study tested the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in ROR2 gene that is important in skeletal development. Nineteen ROR2 SNPs were genotyped in 705 individuals, belonging to 212 nuclear families. The four tagging SNPs (tSNPs) and the pairwise haplotypes between adjacent tSNPs were tested for association with series of hand BL and BMD measurements, adjusted for covariates, using family-based association tests. We observed significant associations with BL and BMD mean values for all 18 studied hand bones (p = 0.0080, 0.0030), mean BL and BMD for proximal phalanges (p = 0.0218, 0.0060) and metacarpal bones (p = 0.0014, 0.0004). In the latter, the association remained significant after correction for multiple testing. The region of the first through the second ROR2 introns is most likely to contain the functional polymorphism/s responsible for the observed associations. Further studies are required to identify the ROR2 functional polymorphism/s affecting bone size and BMD variation.

Autosomal Dominant Osteopetrosis: Clinical Severity and Natural History of 94 Subjects with a Chloride Channel 7 Gene Mutation

Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date. This study was primarily a retrospective cross-sectional analysis of individuals with a ClCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied. We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistry), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a ClCN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/or self-reported responses on a questionnaire that was completed by all subjects. The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype. Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P < 0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) and osteomyelitis (16 vs. 0.9%; P < 0.0001). Severe fractures (defined as > or =10 fractures of any type and/or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time. ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.

Strong association between polymorphisms in ANKH locus and skeletal size traits

Loss of bone strength is the main determinant of bone fragility. Bone strength is directly dependent on bone size (BS). A substantial portion of BS variation is attributable to genetic effects. However, the list of genes and allelic variants involved in the determination of BS variation is far from being complete. Polymorphisms in the ANKH gene have been shown to be associated with radiographic hand BS-related phenotypes. The present study examined the possible association of the ANKH gene with skeletal size and shape in order to test the universality of the ANKH effect on BS traits. Our sample consisted of a total of 212 ethnically homogeneous nuclear families (743 individuals) of European origin. Each individual was measured for body height, weight, and several other anthropometrical measurements, and genotyped for nine polymorphic markers (the average heterozygosity level was 0.4). We observed significant associations with practically all the anthropometrical phenotypes studied. More specifically, we found associations with body weight and height, limb length (P</=0.001; promoter region). After adjustment for body height, we demonstrated the substantial association increase for biacromial breadth (P=0.0012; some 140 kb downstream from ANKH) and vertebral column length (P=0.0008; exons 2-7 region). The majority of the observed associations persisted even after correction for multiple testing. For the first time the reliable evidence in support of universality of ANKH gene polymorphisms effect on bone size was provided.

Sa.43. Role of the HLA DRB1*1501 Risk Haplotype in the Expression of Clinical and Radiographic Phenotypes of Multiple Sclerosis

Sa.43. Role of the HLA DRB1*1501 Risk Haplotype in the Expression of Clinical and Radiographic Phenotypes of Multiple Sclerosis

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene

Background: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these,...

Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by mild to moderate short stature, early-onset of osteoarthritis (OA) mainly in the hip and knee joints, and abnormally small and/or irregular epiphyses. MED is clinically and genetically heterogeneous. Six causative genes of MED have been reported, including type IX collagen genes (COL9A1, COL9A2, COL9A3). All the type IX collagen mutations previously reported cause exon skipping that loses the COL3 domain. Here we have identified a novel COL9A3 mutation co-segregating in a three-generation family with MED. The mutation (IVS3 + 5G > A) was speculated to lose the COL3 domain by skipping of exon 3, which was confirmed by in vitro analysis. The patients were of normal height and had minimal complaints with phenotypes being more severe in male patients. The radiographic phenotypes of the patients were relatively milder than those of previously reported cases, and were indistinguishable to common, idiopathic OA.

Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna

Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH) 2 vitamin D was very low (14 pM; N: 40–140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33–105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

Association of birth weight with osteoporosis and osteoarthritis in adult twins.

Twin studies present a unique opportunity to examine the association of birth weight with adult life phenotypes in a design that naturally accounts for maternal factors and a range of early environmental factors, which might potentially bias the association. In this study, we explored the association of birth weight with osteoporosis (OP) and osteoarthritis (OA), in a large national cohort of female twins. Intra-pair differences between the reported birth weight of the twins (n=4008) were examined for an association with: (i) intra-pair differences in bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine, hip and forearm using linear regression; and (ii) osteoarthritis status in pairs discordant for radiographic disease at the hand, hip and knee using matched logistic regression. The confounding influences of height and weight were taken into account. The mean age of the twins was 47.5+/-12.3 yr. Intra-pair differences in birth weight were significantly associated with BMD at the spine (P=0.047), total hip (P=0.016) and femoral neck (P<0.001), but not at the forearm (P=0.245). These were entirely explained by the birth weight association with height and weight. The associations of intra-pair differences in birth weight and BMC were highly significant (P<0.001) at all sites, but were partly explained by adjustment for adult height and weight. We found no clear association between intra-pair birth weight differences and OA in twins discordant for any of the radiographic OA phenotypes at any site. Bone mass and especially BMC are highly associated with birth weight. These associations are accounted for mainly by environmental factors that are independent of maternal factors such as gestational age, maternal smoking and nutrition, and are largely mediated by skeletal size and particularly adult height. Birth weight does not appear to be a major influence on the later development of radiographic OA in women.

Evidence That Smith-McCort Dysplasia and Dyggve-Melchior-Clausen Dysplasia Are Allelic Disorders That Result from Mutations in a Gene on Chromosome 18q12

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.

Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype

Multiple epiphyseal dysplasia (MED) is an osteochondrodysplasia characterized clinically by mild short stature and early-onset degenerative joint disease and radiographically by epiphyseal hypoplasia/dysplasia. MED is genetically heterogeneous, with autosomal dominant cases resulting from mutations in at least three genes: the cartilage oligomeric matrix protein (COMP) gene (EDM1) and the COL9A2 (EDM2) and COL9A3 (EDM3) genes of type IX procollagen. We present here a comparison of the radiographic phenotypes of MED patients with type IX collagen gene mutations and those with COMP gene mutations. We reviewed radiographs from two patients with MED produced by COMP mutations, two families with COL9A2 mutations, and one family with a mutation in COL9A3. The data demonstrated that the patients with type IX collagen defects had more severe joint involvement at the knees and relative hip sparing, while the patients with COMP mutations had significant involvement at the capital femoral epiphyses and irregular acetabuli. This pattern of joint involvement was consistent regardless of overall degree of severity of the phenotype.

Correlation of clinical and molecular biological abnormalities in osteogenesis imperfecta.

Substitution of a glycine residue in the triple helix of the alpha 1(I) chain by either arginine, valine or alanine was associated with the type II lethal perinatal osteogenesis imperfecta phenotype. This phenotype was also produced by a frameshift mutation that resulted in an abnormal amino acid sequence of the carboxy-terminal propeptide of the pro-alpha 1(I) chain. The latter baby, however, showed some clinical and radiographic differences from the other babies with type II OI. The severity of the clinical and radiographic phenotypes are likely to be determined by both the type and site of the mutation as well as by the intra-uterine environment.

HIP DYSPLASIA IN THE AFGHAN HOUND*

In evaluation of pelvic radiographs and necropsy specimens of 3 litters of Afghan Hound puppies resulting from matings of dysplastic parents a spectrum of radiographic phenotypes similar to that reported in other breeds was found. The percentage of dysplastic offspring (75% and 71%) and age at which the diagnosis of canine hip dysplasia could be made (28.5% at 6; 67% at 12; 90.5%at 18; 95% at 35; and 100% at 36 months of age) was also similar to that reported for other breeds. Hip dysplasia in the Afghan Hound is similar in radiographic appearance to hip dysplasia in other breeds despite the low. incidence of this condition among Afghan Hounds. The inheritance of hip dysplasia appeared to be the same in Afghan Hounds as that reported in other breeds